sirolimussirolimus

Sirolimus is a relatively new Sirolimus is a relatively new immunosuppressant drug used to prevent immunosuppressant drug used to prevent rejectionrejection in in organ transplantationorgan transplantation, and is , and is especially useful in especially useful in kidneykidney transplants. It is transplants. It is also known as rapamycin. Sirolimus is a also known as rapamycin. Sirolimus is a macrolidemacrolide antibioticantibiotic ( ("-mycin""-mycin") first ) first discovered as a product of the bacterium discovered as a product of the bacterium Streptomyces hygroscopicusStreptomyces hygroscopicus in a soil in a soil sample from an island called sample from an island called Rapa NuiRapa Nui. . Rapamycin originally was developed as an Rapamycin originally was developed as an antifungal agent. However,when it was antifungal agent. However,when it was discovered rapamycin had potent discovered rapamycin had potent immunosuppressive. immunosuppressive.

Chemical structure:Chemical structure:Formula C51 C79 NO31Formula C51 C79 NO31

Physical properties:Physical properties: Names:Names:Rapamycin , sirolimus , rapamuneRapamycin , sirolimus , rapamune

Melting pointMelting point 183-185 C 183-185 C Mol. Wt.Mol. Wt. 914.18 914.18

Mechanism of Action:Mechanism of Action:RAPA blocks T lymphocyte proliferation . RAPA’s effects are RAPA blocks T lymphocyte proliferation . RAPA’s effects are not limited to IL-2- or IL-4 mediated growth of T cells, as it has not limited to IL-2- or IL-4 mediated growth of T cells, as it has been found to inhibit IL-12 , IL-7, and IL-15 driven proliferation been found to inhibit IL-12 , IL-7, and IL-15 driven proliferation of activated T cells of activated T cells RAPA blocks cell cycle progression in mid-to-late G1 phase , RAPA blocks cell cycle progression in mid-to-late G1 phase , RAPA blocks lymphocyte proliferation . RAPA inhibits IL-2 RAPA blocks lymphocyte proliferation . RAPA inhibits IL-2 dependent and independent proliferation of purified normal dependent and independent proliferation of purified normal human B lymphocytes stimulated with human B lymphocytes stimulated with Staphylococcus aureus Staphylococcus aureus (SA) . It also prevents SA and IL-2 or IL-6 dependent (SA) . It also prevents SA and IL-2 or IL-6 dependent differentiation into antibody-producing cells, thereby differentiation into antibody-producing cells, thereby decreasing IgM, IgG and IgA production . decreasing IgM, IgG and IgA production . SRL binding to specific cytosolic binding proteins called SRL binding to specific cytosolic binding proteins called immunophilins (FKBPs).immunophilins (FKBPs).This complex inhipits isomerase activity (PPlase).This complex inhipits isomerase activity (PPlase).FKBP 12 is the most relevant binding protein for the FKBP 12 is the most relevant binding protein for the immunosuppressive effects of RAPAimmunosuppressive effects of RAPA..

Pharmacokinetics:Pharmacokinetics:1-Adminstration1-Adminstration::Oral solution or tablets.Oral solution or tablets.2-Absorption:2-Absorption:SRL reaches maximum concentration in the blood in 2 h with SRL reaches maximum concentration in the blood in 2 h with the solution, compared to 6 h with the tablet formulation.the solution, compared to 6 h with the tablet formulation.Oral bioavailability is low (around 15% when administered Oral bioavailability is low (around 15% when administered with cyclosporine A (CsA)).with cyclosporine A (CsA)).3-distribution3-distribution::Due to its lipophilic nature, SRL is extensively distributed to Due to its lipophilic nature, SRL is extensively distributed to fatty tissues and so has a large volume of distribution (5.6–fatty tissues and so has a large volume of distribution (5.6–16.7 L/kg). Within plasma, SRL is extensively bound to plasma 16.7 L/kg). Within plasma, SRL is extensively bound to plasma proteins. SRL has a long half-life (60 h) so, whenproteins. SRL has a long half-life (60 h) so, whencommencing SRL, a loading dose is necessary.commencing SRL, a loading dose is necessary.4-metabolism:4-metabolism:The metabolites of SRL are inactive .Sirolimus is metabolized The metabolites of SRL are inactive .Sirolimus is metabolized by the cytochrome P450–3A4 Isoenzyme so its effected by by the cytochrome P450–3A4 Isoenzyme so its effected by enzyme inducers &inhibitor. The clearance of SRL enzyme inducers &inhibitor. The clearance of SRL approximates that of liver blood flow, so dose reductions may approximates that of liver blood flow, so dose reductions may be needed in patients with hepatic impairment.be needed in patients with hepatic impairment.5-excretion5-excretion::SRL is excreted by the liverSRL is excreted by the liver..

Pharmacological Action:Pharmacological Action:*Sirolimus does not block IL production by activated T cells *Sirolimus does not block IL production by activated T cells but instead blocks the response of T cells to cytokines.but instead blocks the response of T cells to cytokines.*It is a potent inhibitor of B cell proliferation *It is a potent inhibitor of B cell proliferation &immunoglobulin&immunoglobulinProduction.Production.*Sirolimus also inhibits the mononuclear cell proliferative *Sirolimus also inhibits the mononuclear cell proliferative response to colony stimulation factors &suppresses response to colony stimulation factors &suppresses hematopoietic recovery after myelotoxic treatment in mice .hematopoietic recovery after myelotoxic treatment in mice .* sirolimus displayed comparatively lower platelet and white * sirolimus displayed comparatively lower platelet and white blood cell counts .blood cell counts .

* SRL increases total cholesterol, LDL, triglycerides, apoB- * SRL increases total cholesterol, LDL, triglycerides, apoB- 100, and apoC-III; these effects are repeatable, dose-100, and apoC-III; these effects are repeatable, dose-dependent and reversible.dependent and reversible.* Sirolimus causes anaemia, thrombocytopaenia and * Sirolimus causes anaemia, thrombocytopaenia and leukopaenia due to bone marrow suppressionleukopaenia due to bone marrow suppression..

Sirolimus in CVS:Sirolimus in CVS: SRL has not been SRL has not been shown so far to increase shown so far to increase cardiovascular morbidity or mortality but cardiovascular morbidity or mortality but SRL may improve the cardiovascular risk of SRL may improve the cardiovascular risk of patients post-transplantation.patients post-transplantation. In cardiac In cardiac allograft recipients treated with CsA and allograft recipients treated with CsA and steroids, SRL was found to be superior to steroids, SRL was found to be superior to azathioprine in preventing cardiac transplant azathioprine in preventing cardiac transplant vasculopathy.vasculopathy. SRL is associated with less SRL is associated with less hypertension compared to CNI-based hypertension compared to CNI-based regimes and may be less diabetogenic, but regimes and may be less diabetogenic, but does increase lipid levelsdoes increase lipid levels. .

Therapeutic Uses:Therapeutic Uses: A- In Adult:A- In Adult:1- Kidney1- Kidney ::sirolimus as a primary agent with cyclosporine and sirolimus as a primary agent with cyclosporine and prednisone reduced the overall incidence of acute prednisone reduced the overall incidence of acute allograft rejection episodes from 32 to 7.5%. allograft rejection episodes from 32 to 7.5%.

2-Islet:2-Islet:In a widely heralded initial experience, reported the In a widely heralded initial experience, reported the successful use of sirolimus as a primary successful use of sirolimus as a primary immunosuppressive agent in seven patients with immunosuppressive agent in seven patients with type 1 diabetes who underwent islet cell type 1 diabetes who underwent islet cell transplantation. This glucocorticoid-free regimen transplantation. This glucocorticoid-free regimen combined sirolimus, tacrolimus, and daclizumab.combined sirolimus, tacrolimus, and daclizumab. 3-liver:3-liver:Sirolimus has been used in combination with Sirolimus has been used in combination with tacrolimus after liver transplantation to allow the tacrolimus after liver transplantation to allow the subtherapeutic use of tacrolimussubtherapeutic use of tacrolimus . .

B-In Children:B-In Children:Pharmacokinetics different in children compared Pharmacokinetics different in children compared with adults.with adults.Half-life (h) of sirolimus is shorter in children Half-life (h) of sirolimus is shorter in children because of rapid metabolism and some children because of rapid metabolism and some children may need twice a day dosing .may need twice a day dosing .1-Kidney:1-Kidney:Studies in children using sirolimus for primary Studies in children using sirolimus for primary immunosuppression are still limited.immunosuppression are still limited.

2-Liver:2-Liver:Sirolimus was used as primary immunosuppression Sirolimus was used as primary immunosuppression in combination with subtherapeutic tacrolimus.in combination with subtherapeutic tacrolimus.

3- Intestine:3- Intestine:Addition of sirolimus to a tacrolimus decreased Addition of sirolimus to a tacrolimus decreased early rejection and improved graft survival in early rejection and improved graft survival in children and adults receiving intestinal transplants children and adults receiving intestinal transplants

compared with controlcompared with control..

C- In Cancer: C- In Cancer: The anti-proliferative effects of The anti-proliferative effects of sirolimus may have a role in treating sirolimus may have a role in treating cancer. Recently, it was shown that cancer. Recently, it was shown that sirolimus inhibited the progression of sirolimus inhibited the progression of dermal dermal Kaposi's sarcomaKaposi's sarcoma in patients in patients with renal transplantswith renal transplants.. As with all immunosuppressive As with all immunosuppressive medications, rapamycin decreases the medications, rapamycin decreases the body's inherent anti-cancer activity body's inherent anti-cancer activity and allows some cancers which would and allows some cancers which would have been naturally destroyed to have been naturally destroyed to

proliferateproliferate. .

Adverse Effect: Adverse Effect: A- Major Adverse Effect:A- Major Adverse Effect:1- Hyperlipidaemia:1- Hyperlipidaemia:A major effect on lipid metabolism.A major effect on lipid metabolism.SRL increases total cholesterol, LDL, triglycerides, SRL increases total cholesterol, LDL, triglycerides, apoB- 100, and apoC-III; these effects are apoB- 100, and apoC-III; these effects are repeatable, dose-dependent and reversible.repeatable, dose-dependent and reversible.

2-Wound Complications:2-Wound Complications: Sirolimus is associated with a high wound Sirolimus is associated with a high wound complication in the early stages post-complication in the early stages post-transplantation, with rates varying between 6–15% transplantation, with rates varying between 6–15% due to its anti-proliferative propertiesdue to its anti-proliferative propertiesWound complications include delayed wound Wound complications include delayed wound healing, lymphocoele, haematoma, incisional hernia healing, lymphocoele, haematoma, incisional hernia and relaparotomy for wound complicationand relaparotomy for wound complication..

33 - -Haematological:Haematological:Sirolimus causes anaemia, thrombocytopaenia and Sirolimus causes anaemia, thrombocytopaenia and leukopaenia due to bone marrow suppression, but leukopaenia due to bone marrow suppression, but rarely leads to discontinuation of therapy.rarely leads to discontinuation of therapy.4- Thrombosis:4- Thrombosis:SRL was not associated with an increased risk of SRL was not associated with an increased risk of deep vein thrombosis (DVT), but the DVT that did deep vein thrombosis (DVT), but the DVT that did develop were preceded by lymphocoele in develop were preceded by lymphocoele in threequartersof cases.threequartersof cases.5-Oral Ulcers:5-Oral Ulcers:Initially, it was assumed that these aphthous ulcers Initially, it was assumed that these aphthous ulcers were due to herpes simplex infection but this has were due to herpes simplex infection but this has not been confirmed and it is now assumed that they not been confirmed and it is now assumed that they result from a direct toxic effect of SRL.result from a direct toxic effect of SRL.6- Lung Toxicity:6- Lung Toxicity:In a phase II trial of SRL, an increased incidence of In a phase II trial of SRL, an increased incidence of Pneumocystis carinii Pneumocystis carinii pneumonia (PCP) was reported pneumonia (PCP) was reported in a singlein a single centre that did not use routine PCP centre that did not use routine PCP prophylaxisprophylaxis. .

Drug – Drug Interaction:Drug – Drug Interaction: Sirolimus and CNI are both metabolized by the Sirolimus and CNI are both metabolized by the cytochrome p450 3A4 isoenzyme.cytochrome p450 3A4 isoenzyme.SRL blood concentration is 30% higher with CsA SRL blood concentration is 30% higher with CsA To minimize this interaction, SRLshould be given 4 To minimize this interaction, SRLshould be given 4 h after CsA.h after CsA. SRL does not appear to have a pharmacokinetic SRL does not appear to have a pharmacokinetic interaction with tacrolimus.interaction with tacrolimus. Mycophenolic acid AUC is higher when SRL and Mycophenolic acid AUC is higher when SRL and mycophenolate mofetil (MMF) does not affect SRL mycophenolate mofetil (MMF) does not affect SRL exposure.exposure.compared to co-administration of SRL and CsA.compared to co-administration of SRL and CsA.Enzymes inhibitor increase its concentration .Enzymes inhibitor increase its concentration .Enzymes inducer decrease its concentrationEnzymes inducer decrease its concentration . .

Dosage:Dosage: The maintenance sirolimus doses ranged from 0.5 The maintenance sirolimus doses ranged from 0.5 to 15 mg once daily .to 15 mg once daily .The dose was only reduced in the presence of drug The dose was only reduced in the presence of drug –indused toxicity.–indused toxicity.

Missed Dose:Missed Dose: Do not double doses.Do not double doses.If you miss a dose of sirolimus and remember it If you miss a dose of sirolimus and remember it within 12 hours, take the missed dose as soon as within 12 hours, take the missed dose as soon as you remember. However, if it is almost time for the you remember. However, if it is almost time for the next dose, skip the missed dose, go back to your next dose, skip the missed dose, go back to your regular dosing schedule, and check with your regular dosing schedule, and check with your doctordoctor..

Sirolimus Monotherapy:Sirolimus Monotherapy: Monotherapy to 29 primary renal transplant Monotherapy to 29 primary renal transplant patients show acute rejection developed in patients show acute rejection developed in eightout of 29 (five of which were antibody-eightout of 29 (five of which were antibody-mediated). One graft was lost to rejection. mediated). One graft was lost to rejection. All other patients tolerated therapy well.All other patients tolerated therapy well.Combination Therapy: Combination Therapy: A-with CsA:A-with CsA:show reduction in the incidence of acute show reduction in the incidence of acute allograft rejection episodes to 7.5% over3 allograft rejection episodes to 7.5% over3 years.years.

B-with tacrolimus:B-with tacrolimus: SRL and TRL might compete for FK-binding SRL and TRL might compete for FK-binding proteins (FKBP), producing antagonistic proteins (FKBP), producing antagonistic effects , the large amount of cytosolic FKBP effects , the large amount of cytosolic FKBP seems to obviate this possibilityseems to obviate this possibility..